scispace - formally typeset
Search or ask a question

Showing papers in "The Journal of Clinical Endocrinology and Metabolism in 2004"


Journal ArticleDOI
TL;DR: An overview of the endocrine functions of adipose tissue can be found in this paper, where the authors highlight the adverse metabolic consequences of both adipose excess and deficiency, and propose a more rational therapy for these increasingly prevalent disorders.
Abstract: Adipose tissue is a complex, essential, and highly active metabolic and endocrine organ. Besides adipocytes, adipose tissue contains connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. Together these components function as an integrated unit. Adipose tissue not only responds to afferent signals from traditional hormone systems and the central nervous system but also expresses and secretes factors with important endocrine functions. These factors include leptin, other cytokines, adiponectin, complement components, plasminogen activator inhibitor-1, proteins of the renin-angiotensin system, and resistin. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by the adverse metabolic consequences of both adipose tissue excess and deficiency. A better understanding of the endocrine function of adipose tissue will likely lead to more rational therapy for these increasingly prevalent disorders. This review presents an overview of the endocrine functions of adipose tissue.

5,484 citations


Journal ArticleDOI
TL;DR: Data from a large representative unselected population support the concept that PCOS is the most common endocrine abnormality of reproductive-aged women in the United States.
Abstract: Notwithstanding the potential public health impact of the polycystic ovary syndrome (PCOS), estimates regarding its prevalence are limited and unclear. Between July 1998 and October 1999, 400 unselected consecutive premenopausal women (18-45 yr of age) seeking a preemployment physical at the University of Alabama at Birmingham were studied (223 Black, 166 White, and 11 of other races). Evaluation included a history and physical examination, a modified Ferriman-Gallwey hirsutism score, and serum screening for hyperandrogenemia, hyperprolactinemia, and 21-hydroxylase-deficient nonclassical adrenal hyperplasia. PCOS was diagnosed by the presence of the following: 1) oligoovulation, 2) hyperandrogenemia and/or hirsutism (modified Ferriman-Gallwey score > or = 6), and 3) the exclusion of related disorders. Confirmed PCOS was established in those individuals whose evaluation was complete and indicative of PCOS, and possible PCOS was established when the hormonal evaluation was not complete or was unavailable, but the clinical phenotype was otherwise suggestive of the disorder. The individual probability of PCOS in women with possible PCOS was assigned a weight based on the findings in similar subjects whose evaluation was complete, and the total number of PCOS cases arising from these individuals was calculated (i.e. individual probability of PCOS x total number of subjects in the group). The cumulative prevalence of PCOS in our population was 6.6% (26.5 of 400), including 15 subjects among the 347 women completing their evaluation and a calculated prevalence of 11.5 subjects among the remainder. The prevalence rates of PCOS for Black and White women were 8.0 and 4.8%, respectively, not significantly different. These data from a large representative unselected population support the concept that PCOS is the most common endocrine abnormality of reproductive-aged women in the United States.

2,391 citations


Journal ArticleDOI
TL;DR: The release of cytokines from the fat cell may stimulate the proinflammatory state that characterizes obesity, and the combined effect of these pathogenetic consequences of increased fat stores is an increased risk of shortened life expectancy.
Abstract: Obesity is an epidemic disease that threatens to inundate health care resources by increasing the incidence of diabetes, heart disease, hypertension, and cancer. These effects of obesity result from two factors: the increased mass of adipose tissue and the increased secretion of pathogenetic products from enlarged fat cells. This concept of the pathogenesis of obesity as a disease allows an easy division of disadvantages of obesity into those produced by the mass of fat and those produced by the metabolic effects of fat cells. In the former category are the social disabilities resulting from the stigma associated with obesity, sleep apnea that results in part from increased parapharyngeal fat deposits, and osteoarthritis resulting from the wear and tear on joints from carrying an increased mass of fat. The second category includes the metabolic factors associated with distant effects of products released from enlarged fat cells. The insulin-resistant state that is so common in obesity probably reflects the effects of increased release of fatty acids from fat cells that are then stored in the liver or muscle. When the secretory capacity of the pancreas is overwhelmed by battling insulin resistance, diabetes develops. The strong association of increased fat, especially visceral fat, with diabetes makes this consequence particularly ominous for health care costs. The release of cytokines, particularly IL-6, from the fat cell may stimulate the proinflammatory state that characterizes obesity. The increased secretion of prothrombin activator inhibitor-1 from fat cells may play a role in the procoagulant state of obesity and, along with changes in endothelial function, may be responsible for the increased risk of cardiovascular disease and hypertension. For cancer, the production of estrogens by the enlarged stromal mass plays a role in the risk for breast cancer. Increased cytokine release may play a role in other forms of proliferative growth. The combined effect of these pathogenetic consequences of increased fat stores is an increased risk of shortened life expectancy.

1,600 citations


Journal ArticleDOI
TL;DR: The variable characteristics of obesity are examined; this will be followed by an examination of the relation of obesity to the metabolic syndrome; and the relationship of the metabolic Syndrome to ASCVD will be reviewed.
Abstract: Obesity is rampant in the United States and is becoming increasing common worldwide. The increase in obesity prevalence is due to two major factors, plentiful supplies of inexpensive foods and sedentary jobs. Both are driven in no small part by technology. Thanks to technology, production of large quantities of cheap food is possible, and manual work is rapidly disappearing. In areas of the world in which these advances have not penetrated, obesity is not a significant public health problem. Thus, obesity is a direct result of technological advance and represents a major challenge for technological society. Obesity must also be recognized as a product of free society in which a multitude of food choices and job opportunities are available. A public health approach to the problem of obesity that restricts choice will not be acceptable to a free society. This fact puts increased responsibility on the individual to recognize the underlying causes of obesity and modify behavior to reduce the personal burden of obesity. That obesity extracts a social cost is well recognized. The costs in physical health are less well recognized by the general public. The foremost physical consequence of obesity is atherosclerotic cardiovascular disease (ASCVD) (1). A substantial portion of the ASCVD resulting from obesity is mediated by type 2 diabetes. But obesity is accompanied by several other risk factors for ASCVD. The sum of the risk factors that predisposes to ASCVD goes by the name of metabolic syndrome. In addition, obesity is accompanied by other medical complications other than ASCVD and diabetes; these include fatty liver, cholesterol gallstones, sleep apnea, osteoarthritis, and polycystic ovary disease. These disorders are commonly found in individuals who carry the metabolic syndrome. Obesity can be called an underlying risk factor for cardiovascular disease (ASCVD) (2). It is called this because it raises the risk for ASCVD through other risk factors. The latter include the major risk factors (hypercholesterolemia, hypertension, hyperglycemia) and emerging risk factors (atherogenic dyslipidemia, insulin resistance, proinflammatory state, prothrombotic state). The relationship of obesity to major and emerging risk factors varies, depending on the genetic and acquired characteristics of individuals. The majority of obese persons who develop ASCVD typically have a clustering of major and emerging risk factors (metabolic syndrome). The constellation of major and emerging risk factors that make up the metabolic syndrome can be called metabolic risk factors (3). This article will first examine the variable characteristics of obesity; this will be followed by an examination of the relation of obesity to the metabolic syndrome; and finally, the relation of the metabolic syndrome to ASCVD will be reviewed. Categories of obesity Obesity can be defined as an excess of body fat. A surrogate marker for body fat content is the body mass index (BMI), which is determined by weight (kilograms) divided by height squared (square meters). In clinical terms, a BMI of 25–29 kg/m 2 is called overweight; higher BMIs (30 kg/m 2 ) are called obesity (4). A better way to define obesity would be in terms of percent total body fat (4). This can be measured by several methods (skin-fold thickness, bioelectrical impedance, underwater weighing). In terms of percent body fat, obesity can be defined as 25% or greater in men and 35% or greater in women. The measurement of percent body fat is rarely used in clinical practice, however, because of inconvenience and cost.

1,186 citations


Journal ArticleDOI
TL;DR: Physicians resorting to use of vitamin D(2) should be aware of its markedly lower potency and shorter duration of action relative to vitamin D (3), with the relative potencies for D(3) being 9.5:1.
Abstract: Vitamins D2 and D3 are generally considered to be equivalent in humans. Nevertheless, physicians commonly report equivocal responses to seemingly large doses of the only high-dose calciferol (vitamin D2) available in the U.S. market. TherelativepotenciesofvitaminsD2andD3wereevaluated by administering single doses of 50,000 IU of the respective calciferols to 20 healthy male volunteers, following the time course of serum vitamin D and 25-hydroxyvitamin D (25OHD) over a period of 28 d and measuring the area under the curve of the rise in 25OHD above baseline. The two calciferols produced similar rises in serum concentration of the administered vitamin, indicating equivalent absorption. Both produced similar initial rises in serum 25OHD over the first 3 d, but 25OHD continued to rise in the D3-treated subjects, peaking at 14 d, whereas serum 25OHD fell rapidly in the D2-treated subjects and was not different from baseline at 14 d. Area under the curve (AUC) to d 28 was 60.2ngd/ml(150.5nmold/liter)forvitaminD2and204.7(511.8) for vitamin D3 (P < 0.002). Calculated AUC indicated an even greater differential, with the relative potencies for D3:D2 being 9.5:1. Vitamin D2 potency is less than one third that of vitamin D3. Physicians resorting to use of vitamin D2 should be aware of its markedly lower potency and shorter duration of action relative to vitamin D3 .( J Clin Endocrinol Metab 89: 5387–5391, 2004)

1,102 citations


Journal ArticleDOI
TL;DR: Specific identifiable disorders (NCAH, CAH, HAIRAN syndrome, and androgen-secreting neoplasms) were observed in approximately 7% of subjects, whereas functional androgen excess, principally PCOS, was observed in the remainder.
Abstract: The objective of the present study was to estimate the prevalence of the different pathological conditions causing clinically evident androgen excess and to document the degree of long-term success of suppressive and/or antiandrogen hormonal therapy in a large consecutive population of patients. All patients presenting for evaluation of symptoms potentially related to androgen excess between October 1987 and June 2002 were evaluated, and the data were maintained prospectively in a computerized database. For the assessment of therapeutic response, a retrospective review of the medical chart was performed, after the exclusion of those patients seeking fertility therapy only, or with inadequate follow-up or poor compliance. A total of 1281 consecutive patients were seen during the study period. Excluded from analysis were 408 patients in whom we were unable to evaluate hormonal status, determine ovulatory status, or find any evidence of androgen excess. In the remaining population of 873 patients, the unbiased prevalence of androgen-secreting neoplasms was 0.2%, 21-hydroxylase-deficient classic adrenal hyperplasia (CAH) was 0.6%, 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) was 1.6%, hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome was 3.1%, idiopathic hirsutism was 4.7%, and polycystic ovary syndrome (PCOS) was 82.0%. Fifty-nine (6.75%) patients had elevated androgen levels and hirsutism but normal ovulation. A total of 257 patients were included in the assessment of the response to hormonal therapy. The mean duration of follow-up was 33.5 months (range, 6-155). Hirsutism improved in 86%, menstrual dysfunction in 80%, acne in 81%, and hair loss in 33% of patients. The major side effects noted were irregular vaginal bleeding (16.1%), nausea (13.0%), and headaches (12.6%); only 36.6% of patients never complained of side effects. In this large study of consecutive patients presenting with clinically evident androgen excess, specific identifiable disorders (NCAH, CAH, HAIRAN syndrome, and androgen-secreting neoplasms) were observed in approximately 7% of subjects, whereas functional androgen excess, principally PCOS, was observed in the remainder. Hirsutism, menstrual dysfunction, or acne, but not alopecia, improved in the majority of patients treated with a combination suppressive therapy; although more than 60% experienced side effects.

1,028 citations


Journal ArticleDOI
TL;DR: It is concluded that in young men and women, modest sleep loss is associated with significant sleepiness, impairment of psychomotor performance, and increased secretion of proinflammatory cytokines.
Abstract: Total sleep restriction in humans is associated with increased daytime sleepiness, decreased performance, and hormonal/metabolic disturbances. The effects of mild chronic sleep restriction that mimic real life are not known. To assess the effects of modest sleep restriction from 8 to 6 h/night for 1 wk, 25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecutive nights in the sleep laboratory. After 1 wk of sleep restriction, although subjects’ nighttime sleep was deeper, subjects were significantly sleepier (multiple sleep latency test) and performed worse in four primary variables of psychomotor vigilance test (both P < 0.01). Furthermore, 24-h secretion of IL-6 was increased by 0.8 ± 0.3 pg/ml (P < 0.05) in both sexes, whereas TNFα was increased only in men. Also, the peak cortisol secretion was lower after sleep restriction than at baseline, and this difference was stronger in men (55.18 ± 24.83 nmol/liter; P < 0.05) than in women (35.87 ± 24.83 nmol/liter; P < 0.16). We c...

915 citations


Journal ArticleDOI
TL;DR: Sleep modulates a major component of the neuroendocrine control of appetite, and the effects of sleep duration on leptin were quantitatively associated with alterations of the cortisol and TSH profiles and were accompanied by an elevation of postbreakfast homeostasis model assessment values.
Abstract: Sleep plays an important role in energy homeostasis. The present study tests the hypothesis that circulating levels of leptin, a hormone that signals energy balance to the brain, are influenced by sleep duration. We also analyzed associations between leptin and sympathovagal balance, cortisol, TSH, glucose, and insulin under different bedtime conditions. Twenty-four-hour hormonal and glucose profiles were sampled at frequent intervals, and sympathovagal balance was estimated from heart rate variability in 11 subjects studied after 6 d of 4-h bedtimes (mean +/- sem of sleep duration during last 2 d: 3 h and 49 +/- 2 min) and after 6 d of 12-h bedtimes (sleep: 9 h and 03 +/- 15 min). A study with 8-h bedtimes was performed 1 yr later (sleep: 6 h and 52 +/- 10 min). Caloric intake and activity levels were carefully controlled in all studies. Mean levels, maximal levels, and rhythm amplitude of leptin were decreased (-19%, -26%, and -20%, respectively) during sleep restriction compared with sleep extension. The decrease in leptin levels was concomitant with an elevation of sympathovagal balance. The effects of sleep duration on leptin were quantitatively associated with alterations of the cortisol and TSH profiles and were accompanied by an elevation of postbreakfast homeostasis model assessment values. Measures of perceived stress were not increased during sleep restriction. During the study with 8-h bedtimes, hormonal and metabolic parameters were intermediate between those observed with 4-h and 12-h bedtimes. In conclusion, sleep modulates a major component of the neuroendocrine control of appetite.

907 citations


Journal ArticleDOI
TL;DR: The wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of primary aldosteronism, which was previously believed to account for less than 1% of hypertensives.
Abstract: Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3-6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28-50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.

861 citations


Journal ArticleDOI
TL;DR: Improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.
Abstract: The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.

707 citations


Journal ArticleDOI
TL;DR: Investigation of the roles of metabolic, body composition, and cardiovascular disease risk in subtypes of obesity finds that a greater understanding of the MHO and MONW individual has important implications for therapeutic decision making, the characterization of subjects in research protocols, and medical education.
Abstract: Obesity is thought to be a heterogeneous disorder with several possible etiologies; therefore, by examining subtypes of obesity we attempt to understand obesity's heterogeneous nature. The purpose of this review was to investigate the roles of metabolic, body composition, and cardiovascular disease risk in subtypes of obesity. We briefly consider two subtypes of obesity that have been identified in the literature. One subset of individuals, termed the metabolically healthy, but obese (MHO), despite having large amounts of fat mass compared with at risk obese individuals shows a normal metabolic profile, but remarkably normal to high levels of insulin sensitivity. Preliminary evidence suggests that this could be due at least in part to lower visceral fat levels and earlier onset of obesity. A second subset, termed the metabolically obese, but normal weight (MONW), present with normal body mass index, but have significant risk factors for diabetes, metabolic syndrome, and cardiovascular disease, which could be due to higher fat mass and plasma triglycerides as well as higher visceral fat and liver content. We also briefly consider the potential role of adipose and gastrointestinal hormonal profiles in MHO and MONW individuals, which could lead to a better understanding of potential factors that may regulate their body composition. This information will eventually be invaluable in helping us understand factors that predispose to or protect obese individuals from metabolic and cardiovascular disease. Collectively, a greater understanding of the MHO and MONW individual has important implications for therapeutic decision making, the characterization of subjects in research protocols, and medical education.

Journal ArticleDOI
TL;DR: Reductions of circulating insulin and leptin and increased ghrelin concentrations, as demonstrated in this study, could lead to increased caloric intake and ultimately contribute to weight gain and obesity during chronic consumption of diets high in fructose.
Abstract: Previous studies indicate that leptin secretion is regulated by insulin-mediated glucose metabolism. Because fructose, unlike glucose, does not stimulate insulin secretion, we hypothesized that meals high in fructose would result in lower leptin concentrations than meals containing the same amount of glucose. Blood samples were collected every 30-60 min for 24 h from 12 normal-weight women on 2 randomized days during which the subjects consumed three meals containing 55, 30, and 15% of total kilocalories as carbohydrate, fat, and protein, respectively, with 30% of kilocalories as either a fructose-sweetened [high fructose (HFr)] or glucose-sweetened [high glucose (HGl)] beverage. Meals were isocaloric in the two treatments. Postprandial glycemic excursions were reduced by 66 +/- 12%, and insulin responses were 65 +/- 5% lower (both P < 0.001) during HFr consumption. The area under the curve for leptin during the first 12 h (-33 +/- 7%; P < 0.005), the entire 24 h (-21 +/- 8%; P < 0.02), and the diurnal amplitude (peak - nadir) (24 +/- 6%; P < 0.0025) were reduced on the HFr day compared with the HGl day. In addition, circulating levels of the orexigenic gastroenteric hormone, ghrelin, were suppressed by approximately 30% 1-2 h after ingestion of each HGl meal (P < 0.01), but postprandial suppression of ghrelin was significantly less pronounced after HFr meals (P < 0.05 vs. HGl). Consumption of HFr meals produced a rapid and prolonged elevation of plasma triglycerides compared with the HGl day (P < 0.005). Because insulin and leptin, and possibly ghrelin, function as key signals to the central nervous system in the long-term regulation of energy balance, decreases of circulating insulin and leptin and increased ghrelin concentrations, as demonstrated in this study, could lead to increased caloric intake and ultimately contribute to weight gain and obesity during chronic consumption of diets high in fructose.

Journal ArticleDOI
TL;DR: Recent work on the vascular actions of adiponectin complements the growing body of information on its insulin-sensitizing effects in glucose and lipid metabolism and is now a recognized component of a novel signaling network among adipocytes, insulin-sensitive tissues, and vascular function that has important consequences for cardiovascular risk.
Abstract: Cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with obesity and type 2 diabetes mellitus, and recent work has elucidated several potential mechanisms by which increased adiposity enhances cardiovascular risk. Excess adipose tissue, especially in certain compartments, leads to reduced insulin sensitivity in metabolically responsive tissues, which is frequently associated with a set of cardiovascular risk factors, including hyperinsulinemia, hypertension, dyslipidemia, and glucose intolerance. Increasing attention has also been paid to the direct vascular effects of plasma proteins that originate from adipose tissue, especially adiponectin, which exhibits potent antiinflammatory and antiatherosclerotic effects. This brief review will summarize recent work on the vascular actions of adiponectin, which complements the growing body of information on its insulin-sensitizing effects in glucose and lipid metabolism. Adiponectin is now a recognized component of a novel signaling network among adipocytes, insulin-sensitive tissues, and vascular function that has important consequences for cardiovascular risk.

Journal ArticleDOI
TL;DR: The recent trends in overweight and obesity are reviewed, the lifestyle factors that influence the increasing prevalence of obesity are summarized, and the health and economic impact of the obesity epidemic is discussed.
Abstract: As the obesity epidemic spreads, concern about the significant health and economic consequences has also grown. Obesity has been linked to a variety of chronic diseases, almost 300,000 deaths each year, and $117 billion in direct and indirect annual costs in the United States alone. In this article we review the recent trends in overweight and obesity, summarize the lifestyle factors that influence the increasing prevalence of obesity, and discuss the health and economic impact of the obesity epidemic.

Journal ArticleDOI
TL;DR: It appears unlikely that elevation in 1,25-vit D concentrations fall with increasing adiposity, which is an important hormonal mechanism causing or maintaining obesity in adults.
Abstract: Several previous reports of small cohorts have found significantly higher serum 1,25-dihydroxy vitamin D (1,25-vit D) in obese compared with nonobese whites. Based on these reports and on recent in vitro studies of adipocytes which suggest that administration of 1,25-vit D can stimulate lipogenesis and inhibit lipolysis, some investigators have proposed that high 1,25-vit D may play a role in promoting or maintaining adipocyte triglyceride stores in obese adults. To test the hypothesis that obesity is commonly associated with increased 1,25-vit D, we examined the relationships between calciotropic hormones and body adiposity in a large cohort of healthy adults. Serum intact PTH, 25-hydroxy vitamin D, and 1,25-vit D were measured in the postabsorptive state in 302 healthy adults who were Caucasian (n = 190; 71% female), African-American (n = 84; 89% female), and of other race/ethnicity (n = 28; 61% female). Results from the 154 obese subjects [body mass index (BMI) 37.3 +/- 5.8 kg/m(2); range, 30.1-58.2 kg/m(2)] were compared with those from 148 nonobese (BMI 25.6 +/- 2.9 kg/m(2); range, 18.0-29.9 kg/m(2)) age-, race-, and sex-matched participants. Body composition was measured by dual energy x-ray absorptiometry. Serum intact PTH was positively correlated with both BMI (r = 0.42; P < 0.0001) and body fat mass (r = 0.37; P < 0.0001). Serum 25-hydroxy vitamin D was negatively correlated with BMI (r = -0.4; P < 0.0001) and body fat mass (r = -0.41; P < 0.0001). Serum 1,25-vit D was also negatively correlated with BMI (r = -0.26; P < 0.0001) and body fat mass (r = -0.25; P = 0.0001). Serum 1,25-vit D was significantly lower in obese than nonobese subjects (105.7 +/- 41.1 vs. 124.8 +/- 36.7 pmol/liter; P < 0.0001) in both Caucasian and African-American adults. We conclude that, because 1,25-vit D concentrations fall with increasing adiposity, it appears unlikely that elevation in 1,25-vit D is an important hormonal mechanism causing or maintaining obesity in adults.

Journal ArticleDOI
TL;DR: Thiazolidinediones enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA, and favorably influence the production of adipocytokines, contributing to improvements in muscle/hepatic insulin sensitivity and pancreatic function in type 2 diabetics.
Abstract: Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance in liver and muscle and impaired insulin secretion. Considerable evidence also implicates deranged adipocyte metabolism and altered fat topography in the pathogenesis of glucose intolerance in T2DM. 1) Fat cells are resistant to insulin’s antilipolytic effect, leading to day-long elevated plasma FFA levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic/muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. 2) Dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory, and atherosclerotic-provoking cytokines and fail to secrete normal amounts of insulin-sensitizing adipocytokines. 3) Enlarged fat cells are insulin resistant and have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid “overflows” into muscle, liver, and perhaps -cells, causing muscle/ hepatic insulin resistance and impaired insulin secretion. Thiazolidinediones enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA, and favorably influence the production of adipocytokines. Thiazolidinediones also redistribute fat within the body (decreased visceral and hepatic fat; increased sc fat) and decrease intracellular concentrations of triglyceride metabolites in muscle, liver, and -cells, contributing to improvements in muscle/hepatic insulin sensitivity and pancreatic function in type 2 diabetics.

Journal ArticleDOI
TL;DR: Testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol in men with symptomatic androgen deficiency.
Abstract: Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha, IL-1beta, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 +/- 1.2 nmol/liter; bioavailable testosterone, 2.4 +/- 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNFalpha (-3.1 +/- 8.3 vs. 1.3 +/- 5.2 pg/ml; P = 0.01) and IL-1beta (-0.14 +/- 0.32 vs. 0.18 +/- 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 +/- 1.8 vs. -1.1 +/- 3.0 pg/ml; P = 0.01); the reductions of TNFalpha and IL-1beta were positively correlated (r(S) = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (-0.25 +/- 0.4 vs. -0.004 +/- 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.

Journal ArticleDOI
TL;DR: Overweight Hispanic youth with a family history for type 2 diabetes are at increased risk for cardiovascular disease and type 1 diabetes, and this appears to be due to decreased insulin sensitivity.
Abstract: The prevalence of the metabolic syndrome is highest among Hispanic adults. However, studies exploring the metabolic syndrome in overweight Hispanic youth are lacking. Subjects were 126 overweight children (8-13 yr of age) with a family history for type 2 diabetes. The metabolic syndrome was defined as having at least three of the following: abdominal obesity, low high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, hypertension, and/or impaired glucose tolerance. Insulin sensitivity was determined by the frequently sampled iv glucose tolerance test and minimal modeling. The prevalence of abdominal obesity, low HDL cholesterol, hypertriglyceridemia, systolic and diastolic hypertension, and impaired glucose tolerance was 62, 67, 26, 22, 4, and 27%, respectively. The presence of zero, one, two, or three or more features of the metabolic syndrome was 9, 22, 38, and 30%, respectively. After controlling for body composition, insulin sensitivity was positively related to HDL cholesterol (P < 0.01) and negatively related to triglycerides (P < 0.001) and systolic (P < 0.01) and diastolic blood pressure (P < 0.05). Insulin sensitivity significantly decreased (P < 0.001) as the number of features of the metabolic syndrome increased. In conclusion, overweight Hispanic youth with a family history for type 2 diabetes are at increased risk for cardiovascular disease and type 2 diabetes, and this appears to be due to decreased insulin sensitivity. Improving insulin resistance may be crucial for the prevention of chronic disease in this at-risk population.

Journal ArticleDOI
TL;DR: It is indicated that reduction of GH to less than 1 microg/liter or normalization of serum IGF-I reduces mortality to expected levels and acts equivalently as predictors of mortality.
Abstract: Studies of acromegaly have shown a doubling of mortality compared with the general population. With the development of new modalities of treatment, it has become important to identify prognostic factors relating to mortality. Between 1964 and 2000, 208 acromegalic patients were followed for a mean of 13 yr at Auckland Hospital. Treatment was by surgery or radionuclide pituitary implantation, and all except 27 patients received pituitary radiation. Over the duration of the study, 72 patients died at a mean age of 61 +/- 12.8 yr. Those dying were significantly older at diagnosis, had a higher prevalence of hypertension and diabetes, and were more likely to have hypopituitarism. The observed to expected mortality ratio (O/E ratio) fell from 2.6 (95% confidence interval, 1.9-3.6) in those with last follow-up GH greater than 5 microg/liter to 2.5 (1.6-3.8), 1.6 (0.9-3), and 1.1 (0.5-2.1) for those with GH less than 5, less than 2, and less than 1 microg/liter, respectively (P < 0.001). Serum IGF-I, expressed as an SD score, was significantly associated with mortality, with O/E mortality ratios of 3.5 (95% confidence interval, 2.8-4.2) for those with an SD score greater than 2, 1.6 (0.6-2.6) for those with an SD score less than 2 (normal or low levels), and 1.0 (0.1-3) for those with an SD score less than zero. When assessed by multivariate analysis, last serum GH (P < 0.001), age, duration of symptoms before diagnosis (P < 0.03), and hypertension (P < 0.04) were independent predictors of survival. If IGF-I was substituted for GH, then survival was independently related to last IGF-I SD score (P < 0.02), indicating that GH and IGF-I act equivalently as predictors of mortality. These findings indicate that reduction of GH to less than 1 microg/liter or normalization of serum IGF-I reduces mortality to expected levels.

Journal ArticleDOI
TL;DR: It is concluded that hypog onadotropic hypogonadism occurs commonly in type 2 diabetes and correlated strongly with cFT but not with SHBG.
Abstract: Type 2 diabetes is associated with lower total testosterone (T) levels in cross-sectional studies. However, it is not known whether the defect is primary or secondary. We investigated the prevalence of hypogonadism in type 2 diabetes by measuring serum total T, free T (FT), SHBG, LH, FSH, and prolactin (PRL) in 103 type 2 diabetes patients. FT was measured by equilibrium dialysis. FT was also calculated by using T and SHBG(cFT).HypogonadismwasdefinedaslowFTorcFT.The mean age was 54.7 1.1 yr, mean body mass index (BMI) was 33.4 0.8 kg/m 2 , and mean HbA1c was 8.4 0.2%. The mean T was 12.19 0.50 nmol/liter (351.7 14.4ng/dl), SHBG was 27.89 1.65 nmol/liter, and FT was 0.250 0.014 nmol/liter. Thirty-three percent of patients were hypogonadal. LH and FSH levels were significantly lower in the hypogonadal group compared with patients with normal FT levels (3.15 0.26 vs. 3.91 0.24 mIU/ml for LH and 4.25 0.45 vs. 5.53 0.40 mIU/ml for FSH; P < 0.05). There was a significant inverse correlation ofBMIwithFT(r–0.382;P<0.01)andT(r–0.327;P<0.01). SHBG correlated inversely with BMI (r –0.267; P < 0.05) but positively with age (r 0.538; P < 0.001) and T (r 0.574; P < 0.001). FT correlated strongly with cFT (r 0.919; P < 0.001) but not with SHBG. LH levels correlated positively with FT (r 0.287; P < 0.05). We conclude that hypogonadotropic hypogonadism occurs commonly in type 2 diabetes. (J Clin Endocrinol Metab 89: 5462–5468, 2004)

Journal ArticleDOI
TL;DR: It is concluded that continued application of AndroGel resulted in beneficial effects similar to those with injectables and other transdermal preparations and monitoring for prostatic disease and assessment for erythrocytosis are strongly advised to reduce the risk of adverse events with T treatment of hypogonadal men.
Abstract: Transdermal testosterone (T) delivery represents an effective alternative to injectable androgens. We studied 163 hypogonadal men who applied 5, 7.5, or 10 g AndroGel (T gel) 1% CIII per day for up to 42 months. Efficacy data were presented in 123 subjects considered evaluable. Continuous AndroGel treatment normalized mean serum T and free T levels. Mean serum 5alpha-dihydrotestosterone concentrations and 5alpha-dihydrotestosterone/T ratio slightly increased, mean serum estradiol/T ratio doubled, and mean serum FSH and LH levels were suppressed by T replacement. Sexual function and mood parameters improved rapidly and were maintained throughout T treatment. Lean body mass increased (P = 0.0001) and fat mass decreased (P = 0.0001), and these changes were maintained with treatment but were not accompanied by significant increases in muscle strength. Increases in serum bone markers suggestive of increased bone formation were followed by gradual and progressive increases in bone mineral density more in the spine (P = 0.0001) than the hip (P = 0.0004). Mild local skin irritation occurred in 12 subjects, resulting in discontinuation in only one subject. Except for the anticipated increase in hematocrit and hemoglobin, there were no clinically significant changes in blood counts or biochemistry. In three subjects with elevated serum prostate-specific antigen, prostate biopsies showed cancer. We conclude that continued application of AndroGel resulted in beneficial effects similar to those with injectables and other transdermal preparations. This study was neither placebo controlled nor powered to determine the effects of T treatment on prostate cancer risk. Thus, monitoring for prostatic disease and assessment for erythrocytosis are strongly advised to reduce the risk of adverse events with T treatment of hypogonadal men.

Journal ArticleDOI
TL;DR: In conclusion, 25OHD assays yield markedly differing results; whether an individual is found to have low or normal vitamin D status is a function of the laboratory used; if the medical community is to make progress in correcting widespread hypovitaminosis D,25OHD measurement must be standardized.
Abstract: Endemic hypovitaminosis D contributes to osteoporosis development. However, variation in 25-hydroxyvitamin D (25OHD) measurement is reported and confounds the diagnosis of vitamin D insufficiency/deficiency. This report emphasizes the marked variability observed in serum 25OHD measurements between laboratories.Initially, postmenopausal women had serum 25OHD determinations: 42 in laboratory A, 20 in laboratory B. Their mean (sem) serum 25OHD concentrations were 46 (2.1) and 21 (2.3) ng/ml in laboratories A and B, respectively. Furthermore, there was little overlap in serum 25OHD among these clinically similar individuals. Specifically, 17% of those measured in laboratory A but 90% in laboratory B were below an arbitrary threshold value of 32 ng/ml.Subsequently, serum was obtained from 10 healthy adults. Two aliquots from each individual, one of which was spiked with 20 ng/ml 25OHD, were sent to six laboratories. Substantial variability was noted between these six laboratories. The mean serum 25OHD concentration ranged from 17.1-35.6 ng/ml. Similarly, the mean increase produced by spiking with 20 ng/ml ranged from 7.7-18.0 ng/ml.In conclusion, 25OHD assays yield markedly differing results; whether an individual is found to have low or normal vitamin D status is a function of the laboratory used. If the medical community is to make progress in correcting widespread hypovitaminosis D, 25OHD measurement must be standardized.

Journal ArticleDOI
TL;DR: The lack of precision and accuracy, together with bias of the immunoassay methods at low serum T concentrations, suggests that the current methods cannot be used to accurately measure T in females or serum from prepubertal subjects.
Abstract: The diagnosis of male hypogonadism requires the demonstration of a low serum testosterone (T) level. We examined serum T levels in pedigreed samples taken from 62 eugonadal and 60 hypogonadal males by four commonly used automated immunoassay instruments (Roche Elecsys, Bayer Centaur, Ortho Vitros ECi and DPC Immulite 2000) and two manual immunoassay methods (DPC-RIA, a coated tube commercial kit, and HUMC-RIA, a research laboratory assay) and compared results with measurements performed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Deming's regression analyses comparing each of the test results with LC-MSMS showed slopes that were between 0.881 and 1.217. The interclass correlation coefficients were between 0.92 and 0.97 for all methods. Compared with the serum T concentrations measured by LC-MSMS, the DPC Immulite results were biased toward lower values (mean difference, -90 +/- 9 ng/dl) whereas the Bayer Centaur data were biased toward higher values (mean difference, +99 +/- 11 ng/dl) over a wide range of serum T levels. At low serum T concentrations (<100 ng/dl or 3.47 nmol/liter), HUMC-RIA overestimated serum T, Ortho Vitros ECi underestimated the serum T concentration, whereas the other two methods (DPC-RIA and Roche Elecsys) showed differences in both directions compared with LC-MSMS. Over 60% of the samples (with T levels within the adult male range) measured by most automated and manual methods were within +/- 20% of those reported by LC-MSMS. These immunoassays are capable of distinguishing eugonadal from hypogonadal males if adult male reference ranges have been established in each individual laboratory. The lack of precision and accuracy, together with bias of the immunoassay methods at low serum T concentrations, suggests that the current methods cannot be used to accurately measure T in females or serum from prepubertal subjects.

Journal ArticleDOI
TL;DR: Estimates of the crude and age-specific prevalence and incidence rates of androgen deficiency in a randomly sampled population-based cohort of middle-aged and older men and projections for the number of cases in the 40- to 69-yr-old U.S. male population were computed.
Abstract: Little is known about the descriptive epidemiology of androgen deficiency. In this study, we sought to address this issue by providing estimates of the crude and age-specific prevalence and incidence rates of androgen deficiency in a randomly sampled population-based cohort of middle-aged and older men. Data on androgen deficiency (defined using both signs/symptoms plus total and calculated free testosterone) were available for n = 1691 (baseline) and n = 1087 (follow-up) men from the Massachusetts Male Aging Study. Crude and age-specific prevalence and incidence rates were calculated. Based on these estimates, projections for the number of cases of androgen deficiency in the 40- to 69-yr-old U.S. male population were computed. Estimates of the crude prevalence of androgen deficiency at baseline and follow-up were 6.0 and 12.3%, respectively. Prevalence increased significantly with age. From baseline age-specific prevalence data, it is estimated that there are approximately 2.4 million 40- to 69-yr-old U.S. males with androgen deficiency. The crude incidence rate of androgen deficiency was 12.3 per 1,000 person-years, and the rate increased significantly (P < 0.0001) with age. Based on these incidence data, we can expect approximately 481,000 new cases of androgen deficiency per year in U.S. men 40-69 yr old.

Journal ArticleDOI
TL;DR: Interventions to prevent islet amyloid formation are emerging, with peptide and small molecule inhibitors being developed that could lead to a preservation of beta-cell mass and amelioration of the islet lesion in type 2 diabetes.
Abstract: Islet amyloid deposition is a pathogenic feature of type 2 diabetes, and these deposits contain the unique amyloidogenic peptide islet amyloid polypeptide. Autopsy studies in humans have demonstrat ...

Journal ArticleDOI
TL;DR: Although RET germline mutation testing has replaced CT for the purpose of determining the presence of carriers of this tumor associated with multiple endocrine neoplasia type 2, the measurement of serum CT has become and has remained the classical clinical marker for MTC.
Abstract: Calcitonin (CT) is a hormone that received its name because of its secretion in response to induced hypercalcemia and its hypocalcemic effect (1). It was shown to originate from the thyroid gland (2). More specifically, the hormone was revealed to be located within the thyroidal parafollicular cells, interspersed within and about the follicular epithelium (3–5). Subsequently termed C cells, they occur primarily in the central region of each lobe of the human thyroid gland (6, 7). These cells, which have CT-containing secretion granules, are neuroendocrine. Embryologically, they originate from the neural crest and migrate to the ultimobranchial glands (8). In mammals, the ultimobranchial glands fuse with the thyroid gland. It was the demonstration that medullary thyroid cancer (MTC) was a malignancy of the C cells (5, 9) that eventually led to the isolation of human CT from this tumor and the determination of its structure (10, 11). Simultaneously, the amino acid sequence of porcine CT was determined (12). Later, the development of immunoassays of serum CT in humans led to the observation that the level of this hormone was increased in the serum of patients with MTC (13–15) and to the demonstration that these levels were further augmented after iv calcium and/or pentagastrin administration (13, 16, 17). These findings had a great impact on the clinical diagnosis, the evaluation of efficacy of surgical extirpation, and the follow-up monitoring of MTC. Although RET germline mutation testing has replaced CT for the purpose of determining the presence of carriers of this tumor associated with multiple endocrine neoplasia type 2 (18, 19), the measurement of serum CT has become and has remained the classical clinical marker for MTC. Immature and mature CT

Journal ArticleDOI
TL;DR: Despite a fairly robust inverse association of adiponectin with breast cancer risk among postmenopausal women, no such significant association between adiponECTin and breast cancer was found among pre menopausal women.
Abstract: Adiponectin, an adipocyte-secreted hormone, is closely and inversely associated with insulin resistance and was recently found to be inversely and independently associated with endometrial cancer. Because insulin resistance in the setting of obesity has also been associated with the development of breast cancer, we have hypothesized that decreased adiponectin levels might underlie the association between breast cancer and obesity/insulin resistance. We evaluated the association of adiponectin with the occurrence of breast cancer in a case-control study comprising 174 women with newly diagnosed, histologically confirmed breast cancer and 167 controls. We found an inverse, fairly strong, and statistically significant association of serum adiponectin with breast cancer (odds ratio, 0.84; 95% confidence interval, 0.71-0.99). Importantly, despite a fairly robust inverse association of adiponectin with breast cancer risk among postmenopausal women (odds ratio, 0.82; 95% confidence interval, 0.67-1.00), no such significant association between adiponectin and breast cancer was found among premenopausal women. The observed associations were independent of possible effects of major components of the IGF system, leptin, body mass index, sociodemographic variables, and known risk factors for breast cancer. Future studies are needed to prove causality and provide further insights into both the mechanisms underlying the actions of this hormone and its potential role in breast cancer.

Journal ArticleDOI
TL;DR: Serum AMH concentrations are elevated in WHO 2 women, especially in those patients exhibiting polycystic ovary syndrome, and may be used as a marker for the extent of the disease.
Abstract: Anti-Mullerian hormone (AMH) concentrations correlate with the number of antral follicles as well as age and constitute an endocrine marker for ovarian aging In normogonadotropic anovulatory infertile women [World Health Organization (WHO) class 2], the number of early antral follicles is usually increased To investigate whether AMH concentrations are increased, serum levels in 128 WHO 2 women were compared with those in 41 normoovulatory premenopausal women of similar age Serum AMH concentrations are significantly (P 10 ml), AMH levels were elevated [93 μg/liter (18–400)], compared with 22 patients without PCOs [64 μg/liter (01–221)] (P < 00001) In WHO 2 patients, AMH concentrations correlated with features characteristic for polycystic ova

Journal ArticleDOI
TL;DR: This work reviews potential insulin sensitizers such as leptin and adiponectin or insulin antagonists such as resistin, TNF, and IL-6 and focuses on certain adipocytokines and how they influence insulin sensitivity.
Abstract: Insulin resistance is defined as a failure of target organs to respond normally to the action of insulin. Insulin resistance causes incomplete suppression of hepatic glucose output and impaired insulin-mediated glucose uptake in the periphery (skeletal muscle and adipose), leading to increased insulin requirements. When increased insulin requirements are not matched by increased insulin levels, hyperglycemia develops. Insulin resistance is also known to be associated with other conditions such as central obesity, hypertension, and dyslipidemia, all risk factors for cardiovascular disease. The constellation of these metabolic abnormalities has been termed the metabolic syndrome. Obesity is a well-recognized risk factor for the development of insulin resistance and the metabolic syndrome. In addition to total amount of fat, distribution of adipose tissue is also important, with visceral depots contributing more to insulin resistance. The mechanisms by which accumulation and anatomic distribution of adipose tissue may be related to the development of insulin resistance are under intense investigation. Adipose tissue has traditionally been considered an energy storage organ, but over the last decade, a novel role of the adipose tissue as an endocrine organ has emerged (1). Adipose tissue is currently known to secrete a large number of factors with diverse functions. These factors include free fatty acids (FFA) with well described physiological and pathophysiological effects on glucose homeostasis (2), and proteins, termed adipocytokines, that act in an autocrine, paracrine, or endocrine fashion to control various metabolic functions (Table 1). Some of these adipocytokines have been implicated in the development of insulin resistance. They may act locally or distally to alter insulin sensitivity in insulin-targeted organs such as muscle and liver or may act through neuroendocrine, autonomic, or immune pathways. Here, we focus on certain adipocytokines and how they influence insulin sensitivity. We review potential insulin sensitizers such as leptin and adiponectin or insulin antagonists such as resistin, TNF, and IL-6. Leptin

Journal ArticleDOI
TL;DR: Because of this body weight regulation system, known as energy homeostasis, nonsurgical methods are notoriously ineffective at achieving major, long-term weight reduction.
Abstract: Energy homeostasis and medical vs. surgical methods to overcome it Obesity is now a global pandemic that continues to accelerate despite the often Herculean efforts by afflicted individuals to lose weight. These efforts are thwarted by a physiological system that regulates body weight in a manner analogous to that by which a thermostat controls ambient temperature. For each individual, there is a highly genetically influenced level of adiposity that is defended by this adipostatic control system, wherein alterations in body fat stores trigger compensatory changes in appetite and energy expenditure that resist weight change (1). It is hypothesized that these processes evolved to defend against malnutrition in times of famine, and hence, the adaptive responses to weight loss appear to be more robust than are those to weight gain (as any dieter can attest). Because of this body weight regulation system, known as energy homeostasis, nonsurgical methods are notoriously ineffective at achieving major, long-term weight reduction. In general, no more than 5–10% of body weight is lost through dieting, exercise, and the few available antiobesity medications, and recidivism after di